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1.
Cell ; 184(15): 4090-4104.e15, 2021 07 22.
Article in English | MEDLINE | ID: mdl-34129837

ABSTRACT

The oral mucosa remains an understudied barrier tissue. This is a site of rich exposure to antigens and commensals, and a tissue susceptible to one of the most prevalent human inflammatory diseases, periodontitis. To aid in understanding tissue-specific pathophysiology, we compile a single-cell transcriptome atlas of human oral mucosa in healthy individuals and patients with periodontitis. We uncover the complex cellular landscape of oral mucosal tissues and identify epithelial and stromal cell populations with inflammatory signatures that promote antimicrobial defenses and neutrophil recruitment. Our findings link exaggerated stromal cell responsiveness with enhanced neutrophil and leukocyte infiltration in periodontitis. Our work provides a resource characterizing the role of tissue stroma in regulating mucosal tissue homeostasis and disease pathogenesis.


Subject(s)
Immunity, Mucosal , Mouth Mucosa/cytology , Mouth Mucosa/immunology , Neutrophils/cytology , Adult , Epithelial Cells/cytology , Gene Expression Regulation , Genetic Predisposition to Disease , Gingiva/pathology , Humans , Inflammation/immunology , Inflammation/pathology , Microbiota , Myeloid Cells/cytology , Periodontitis/genetics , Periodontitis/immunology , Periodontitis/pathology , Single-Cell Analysis , Stromal Cells/cytology , T-Lymphocytes/cytology
2.
Immunity ; 57(4): 859-875.e11, 2024 Apr 09.
Article in English | MEDLINE | ID: mdl-38513665

ABSTRACT

At mucosal surfaces, epithelial cells provide a structural barrier and an immune defense system. However, dysregulated epithelial responses can contribute to disease states. Here, we demonstrated that epithelial cell-intrinsic production of interleukin-23 (IL-23) triggers an inflammatory loop in the prevalent oral disease periodontitis. Epithelial IL-23 expression localized to areas proximal to the disease-associated microbiome and was evident in experimental models and patients with common and genetic forms of disease. Mechanistically, flagellated microbial species of the periodontitis microbiome triggered epithelial IL-23 induction in a TLR5 receptor-dependent manner. Therefore, unlike other Th17-driven diseases, non-hematopoietic-cell-derived IL-23 served as an initiator of pathogenic inflammation in periodontitis. Beyond periodontitis, analysis of publicly available datasets revealed the expression of epithelial IL-23 in settings of infection, malignancy, and autoimmunity, suggesting a broader role for epithelial-intrinsic IL-23 in human disease. Collectively, this work highlights an important role for the barrier epithelium in the induction of IL-23-mediated inflammation.


Subject(s)
Interleukin-23 , Periodontitis , Humans , Epithelial Cells , Inflammation , Toll-Like Receptor 5/metabolism
3.
Immunity ; 46(1): 133-147, 2017 01 17.
Article in English | MEDLINE | ID: mdl-28087239

ABSTRACT

Immuno-surveillance networks operating at barrier sites are tuned by local tissue cues to ensure effective immunity. Site-specific commensal bacteria provide key signals ensuring host defense in the skin and gut. However, how the oral microbiome and tissue-specific signals balance immunity and regulation at the gingiva, a key oral barrier, remains minimally explored. In contrast to the skin and gut, we demonstrate that gingiva-resident T helper 17 (Th17) cells developed via a commensal colonization-independent mechanism. Accumulation of Th17 cells at the gingiva was driven in response to the physiological barrier damage that occurs during mastication. Physiological mechanical damage, via induction of interleukin 6 (IL-6) from epithelial cells, tailored effector T cell function, promoting increases in gingival Th17 cell numbers. These data highlight that diverse tissue-specific mechanisms govern education of Th17 cell responses and demonstrate that mechanical damage helps define the immune tone of this important oral barrier.


Subject(s)
Gingiva/immunology , Immunity, Mucosal/immunology , Immunologic Surveillance/immunology , Mouth Mucosa/immunology , Th17 Cells/immunology , Animals , Flow Cytometry , Gingiva/microbiology , Humans , Mastication , Mice , Mice, Inbred C57BL , Mice, Knockout , Microbiota , Mouth Mucosa/microbiology , Real-Time Polymerase Chain Reaction
4.
PLoS Pathog ; 11(3): e1004698, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25741691

ABSTRACT

Leukocyte Adhesion Deficiency I (LAD-I) is a primary immunodeficiency caused by single gene mutations in the CD18 subunit of ß2 integrins which result in defective transmigration of neutrophils into the tissues. Affected patients suffer from recurrent life threatening infections and severe oral disease (periodontitis). Microbial communities in the local environment (subgingival plaque) are thought to be the triggers for inflammatory periodontitis, yet little is known regarding the microbial communities associated with LAD-I periodontitis. Here we present the first comprehensive characterization of the subgingival communities in LAD-I, using a 16S rRNA gene-based microarray, and investigate the relationship of this tooth adherent microbiome to the local immunopathology of periodontitis. We show that the LAD subgingival microbiome is distinct from that of health and Localized Aggressive Periodontitits. Select periodontitis-associated species in the LAD microbiome included Parvimonas micra, Porphyromonas endodontalis, Eubacterium brachy and Treponema species. Pseudomonas aeruginosa, a bacterium not typically found in subgingival plaque is detected in LAD-I. We suggest that microbial products from LAD-associated communities may have a role in stimulating the local inflammatory response. We demonstrate that bacterial LPS translocates into the lesions of LAD-periodontitis potentially triggering immunopathology. We also show in in vitro assays with human macrophages and in vivo in animal models that microbial products from LAD-associated subgingival plaque trigger IL-23-related immune responses, which have been shown to dominate in patient lesions. In conclusion, our current study characterizes the subgingival microbial communities in LAD-periodontitis and supports their role as triggers of disease pathogenesis.


Subject(s)
Leukocyte-Adhesion Deficiency Syndrome/immunology , Leukocytes/immunology , Periodontitis/microbiology , Porphyromonas gingivalis , Animals , DNA, Bacterial/genetics , DNA, Bacterial/immunology , Dental Plaque/genetics , Humans , Interleukin-23/metabolism , Leukocyte-Adhesion Deficiency Syndrome/metabolism , Leukocyte-Adhesion Deficiency Syndrome/therapy , Mice , Microbiota/immunology , RNA, Ribosomal, 16S/genetics
5.
J Immunol Methods ; 525: 113605, 2024 02.
Article in English | MEDLINE | ID: mdl-38142927

ABSTRACT

Single-cell RNA sequencing and flow cytometry approaches have been instrumental in understanding cellular states within various tissues and organs. However, tissue dissociation methods can potentially alter results and create bias due to preferential recovery of particular cell types. Here we present efforts to optimize methods for dissociation of murine oral mucosal tissues and provide three different protocols that can be utilized to isolate major cell populations in the oral mucosa. These methods can be used both in health and in states of inflammation, such as periodontitis. The optimized protocols use different enzymatic approaches (collagenase II, collagenase IV and the Miltenyi whole skin dissociation kit) and yield preferential recovery of immune, stromal and epithelial cells, respectively. We suggest choosing the dissociation method based on the cell population of interest to study, while understanding the limitations of each approach.


Subject(s)
Mouth Mucosa , Periodontitis , Animals , Mice , Flow Cytometry/methods , Collagenases/metabolism , Inflammation
6.
J Autoimmun ; 40: 122-33, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23110742

ABSTRACT

Sjögren's syndrome is an autoimmune disease that targets exocrine glands, but often exhibits systemic manifestations. Infiltration of the salivary and lacrimal glands by lymphoid and myeloid cells orchestrates a perpetuating immune response leading to exocrine gland damage and dysfunction. Th1 and Th17 lymphocyte populations and their products recruit additional lymphocytes, including B cells, but also large numbers of macrophages, which accumulate with disease progression. In addition to cytokines, chemokines, chitinases, and lipid mediators, macrophages contribute to a proteolytic milieu, underlying tissue destruction, inappropriate repair, and compromised glandular functions. Among the proteases enhanced in this local environment are matrix metalloproteases (MMP) and plasmin, generated by plasminogen activation, dependent upon plasminogen activators, such as tissue plasminogen activator (tPA). Not previously associated with salivary gland pathology, our evidence implicates enhanced tPA in the context of inflamed salivary glands revolving around lymphocyte-mediated activation of macrophages. Tracking down the mechanism of macrophage plasmin activation, the cytokines IFNγ and to a lesser extent, IFNα, via Janus kinase (JAK) and signal transducer and activator of transcription (STAT) activation, were found to be pivotal for driving the plasmin cascade of proteolytic events culminating in perpetuation of the inflammation and tissue damage, and suggesting intervention strategies to blunt irreversible tissue destruction.


Subject(s)
Exocrine Glands/immunology , Exocrine Glands/pathology , Fibrinolysin/metabolism , Sjogren's Syndrome/immunology , Humans , Inflammation/immunology , Interferon-alpha , Interferon-gamma , Janus Kinases/immunology , Janus Kinases/metabolism , Lymphocyte Activation/immunology , Macrophages/immunology , Matrix Metalloproteinase 2/immunology , Matrix Metalloproteinase 9/immunology , Plasminogen/immunology , Plasminogen Activators/metabolism , STAT Transcription Factors/immunology , STAT Transcription Factors/metabolism , Salivary Glands/immunology , Salivary Glands/pathology , Sjogren's Syndrome/pathology , Th1 Cells/immunology , Th17 Cells/immunology
7.
J Infect Dis ; 205(9): 1443-7, 2012 May 01.
Article in English | MEDLINE | ID: mdl-22454462

ABSTRACT

We investigated whether interferon-inducible genes (IFIGs) with known anti-human immunodeficiency virus (HIV) activity in vitro were associated with in vivo virological response in HIV infection. Nine untreated HIV-1-infected volunteers were treated for 12 weeks with peginterferon alfa-2a. A subset of IFIGs (23 of 47) increased compared with baseline through 6 weeks beyond therapy, and 10 of the 23 IFIGs significantly inversely correlated (r = -0.7; P < .05) with virological response. The strength of peginterferon alfa-2a-induced IFIG response significantly correlated with declines in HIV load during treatment (r(2) = 0.87, p = .003). This study links HIV virological response to a specific IFIG subset, a potential prognostic indicator in peginterferon alfa-2a-treated patients with HIV infection.


Subject(s)
Antiviral Agents/administration & dosage , Gene Expression Regulation/drug effects , HIV-1/pathogenicity , Host-Pathogen Interactions/genetics , Interferon-alpha/administration & dosage , Polyethylene Glycols/administration & dosage , HIV Infections/drug therapy , HIV-1/isolation & purification , Humans , Leukocytes, Mononuclear/metabolism , RNA, Viral/genetics , RNA, Viral/isolation & purification , Recombinant Proteins/administration & dosage , Viral Load
8.
J Exp Med ; 220(9)2023 09 04.
Article in English | MEDLINE | ID: mdl-37261457

ABSTRACT

Neutrophil infiltration is a hallmark of periodontitis, a prevalent oral inflammatory condition in which Th17-driven mucosal inflammation leads to destruction of tooth-supporting bone. Herein, we document that neutrophil extracellular traps (NETs) are early triggers of pathogenic inflammation in periodontitis. In an established animal model, we demonstrate that neutrophils infiltrate the gingival oral mucosa at early time points after disease induction and expel NETs to trigger mucosal inflammation and bone destruction in vivo. Investigating mechanisms by which NETs drive inflammatory bone loss, we find that extracellular histones, a major component of NETs, trigger upregulation of IL-17/Th17 responses, and bone destruction. Importantly, human findings corroborate our experimental work. We document significantly increased levels of NET complexes and extracellular histones bearing classic NET-associated posttranslational modifications, in blood and local lesions of severe periodontitis patients, in the absence of confounding disease. Our findings suggest a feed-forward loop in which NETs trigger IL-17 immunity to promote immunopathology in a prevalent human inflammatory disease.


Subject(s)
Extracellular Traps , Periodontitis , Animals , Humans , Histones , Interleukin-17 , Inflammation/pathology , Periodontitis/pathology , Neutrophils/pathology
9.
J Exp Med ; 203(1): 41-6, 2006 Jan 23.
Article in English | MEDLINE | ID: mdl-16418394

ABSTRACT

Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G), a cytidine deaminase, is a recently recognized innate intracellular protein with lethal activity against human immunodeficiency virus (HIV). Packaged into progeny virions, APOBEC3G enzymatic activity leads to HIV DNA degradation. As a counterattack, HIV virion infectivity factor (Vif) targets APOBEC3G for proteasomal proteolysis to exclude it from budding virions. Based on the ability of APOBEC3G to antagonize HIV infection, considerable interest hinges on elucidating its mechanism(s) of regulation. In this study, we provide the first evidence that an innate, endogenous host defense factor has the potential to promote APOBEC3G and rebuke the virus-mediated attempt to control its cellular host. We identify interferon (IFN)-alpha as a potent inducer of APOBEC3G to override HIV Vif neutralization of APOBEC3 proteins that pose a threat to efficient macrophage HIV replication. Our data provide a new dimension by which IFN-alpha mediates its antiviral activity and suggest a means to render the host nonpermissive for viral replication.


Subject(s)
Anti-HIV Agents/pharmacology , HIV-1/pathogenicity , Interferon-alpha/pharmacology , Nucleoside Deaminases/metabolism , Repressor Proteins/metabolism , APOBEC-3G Deaminase , Cells, Cultured , Cytidine Deaminase , Gene Expression , HIV Infections/metabolism , HIV Infections/virology , Humans , Interferon-gamma/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Monocytes/cytology , Monocytes/drug effects , Monocytes/metabolism , Nucleoside Deaminases/genetics , RNA, Small Interfering/genetics , Repressor Proteins/genetics
10.
Am J Pathol ; 178(6): 2866-78, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21641406

ABSTRACT

Differential expression of secretory leukocyte protease inhibitor (SLPI) impacts on tumor progression. SLPI directly inhibits elastase and other serine proteases, and regulates matrix metalloproteinases, plasminogen activation, and plasmin downstream targets to influence invasion. We examined tissues from human oral squamous cell carcinoma (OSCC) for SLPI expression in parallel with proteases associated with tumor progression and evaluated their relationships using tumor cell lines. Significantly decreased SLPI was detected in OSCC compared to normal oral epithelium. Furthermore, an inverse correlation between SLPI and histological parameters associated with tumor progression, including stage of invasion, pattern of invasion, invasive cell grade, and composite histological tumor score was evident. Conversely, elevated plasmin and elastase were positively correlated with histological parameters of tumor invasion. In addition to its known inhibition of elastase, we identify SLPI as a novel inhibitor of plasminogen activation through its interaction with annexin A2 with concomitant reduced plasmin generation by macrophages and OSCC cell lines. In an in vitro assay measuring invasive activity, SLPI blocked protease-dependent tumor cell migration. Our data suggest that SLPI may possess antitumorigenic activity by virtue of its ability to interfere with multiple requisite proteolytic steps underlying tumor cell invasion and may provide insight into potential stratification of oral cancer according to risk of occult metastasis, guiding treatment strategies.


Subject(s)
Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Mouth Neoplasms/metabolism , Mouth Neoplasms/pathology , Secretory Leukocyte Peptidase Inhibitor/metabolism , Aged , Aged, 80 and over , Annexin A2/metabolism , Carcinoma, Squamous Cell/enzymology , Carcinoma, Squamous Cell/genetics , Cell Line, Tumor , Cell Movement , Epithelium/metabolism , Epithelium/pathology , Fibrinolysin/metabolism , Gene Expression Regulation, Neoplastic , Humans , Macrophages/metabolism , Matrix Metalloproteinase Inhibitors , Matrix Metalloproteinases/metabolism , Middle Aged , Mouth Neoplasms/enzymology , Mouth Neoplasms/genetics , Neoplasm Invasiveness , Pancreatic Elastase/metabolism , Plasminogen/metabolism , Secretory Leukocyte Peptidase Inhibitor/antagonists & inhibitors , Secretory Leukocyte Peptidase Inhibitor/genetics
11.
Arthritis Rheum ; 63(10): 3103-15, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21618203

ABSTRACT

OBJECTIVE: Sjögren's syndrome (SS) is a chronic autoimmune disease of unknown etiology that targets salivary and lacrimal glands and may be accompanied by multiorgan systemic manifestations. To further the understanding of immunopathology associated with SS and identify potential therapeutic targets, we undertook the present study comparing the gene expression profiles of salivary glands with severe inflammation versus those of salivary glands with mild or no disease. METHODS: Using microarray profiling of salivary gland tissue from patients with SS and control subjects, we identified target genes, which were further characterized in tissue, serum, and cultured cell populations by real-time polymerase chain reaction and protein analysis. RESULTS: Among the most highly expressed SS genes were those associated with myeloid cells, including members of the mammalian chitinase family, which had not previously been shown to be associated with exocrinopathies. Both chitinase 3-like protein 1 and chitinase 1, highly conserved chitinase-like glycoproteins (one with enzymatic activity and one lacking enzymatic activity), were evident at the transcriptome level and were detected within inflamed tissue. Chitinases were expressed during monocyte-to-macrophage differentiation and their levels augmented by stimulation with cytokines, including interferon-α (IFNα). CONCLUSION: Because elevated expression of these and other macrophage-derived molecules corresponded with more severe SS, the present observations suggest that macrophages have potential immunopathologic involvement in SS and that the tissue macrophage transcription profile reflects multiple genes induced by IFNα.


Subject(s)
Chitinases/metabolism , Macrophages/enzymology , Salivary Glands/enzymology , Sjogren's Syndrome/enzymology , Adult , Chitinases/blood , Chitinases/genetics , Female , Gene Expression , Humans , Male , Middle Aged , RNA, Messenger/genetics , RNA, Messenger/metabolism , Severity of Illness Index
12.
Blood ; 114(9): 1864-74, 2009 Aug 27.
Article in English | MEDLINE | ID: mdl-19556424

ABSTRACT

Infection of CD4(+) chemokine coreceptor(+) targets by HIV is aided and abetted by the proficiency of HIV in eliminating or neutralizing host cell-derived defensive molecules. Among these innate protective molecules, a family of intracellular apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases, is constitutively expressed but inactivated by HIV viral infectivity factor. The ability of interferon-alpha (IFN-alpha) to augment cytidine deaminases offered the possibility that the balance between virus and target cell might be altered in favor of the host. Further characterization of transcriptional profiles induced by IFN-alpha using microarrays, with the intention to identify and dissociate retroviral countermaneuvers from associated toxicities, revealed multiple molecules with suspected antiviral activity, including IL-27. To establish whether IFN-alpha toxicity might be sidestepped through the use of downstream IL-27 against HIV, we examined whether IL-27 directly regulated cytidine deaminases. Although IL-27 induces APOBECs, it does so in a delayed fashion. Dissecting the underlying regulatory events uncovered an initial IL-27-dependent induction of IFN-alpha and/or IFN-beta, which in turn, induces APOBEC3, inhibited by IFN-alpha/beta receptor blockade. In addition to macrophages, the IL-27-IFN-alpha connection is operative in CD4(+) T cells, consistent with an IFN-alpha-dependent pathway underlying host cell defense to HIV.


Subject(s)
CD4-Positive T-Lymphocytes/virology , Gene Expression Regulation , HIV-1/metabolism , Interferon Type I/metabolism , Interleukin-17/physiology , APOBEC Deaminases , CD4-Positive T-Lymphocytes/cytology , Cytidine Deaminase/metabolism , Cytokines/metabolism , Cytosine Deaminase/metabolism , Humans , Interferon-alpha/metabolism , Interferon-beta/metabolism , Interleukin-17/metabolism , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/metabolism , Models, Biological , Oligonucleotide Array Sequence Analysis
13.
STAR Protoc ; 2(4): 100908, 2021 12 17.
Article in English | MEDLINE | ID: mdl-34746866

ABSTRACT

Oral mucosal tissue is composed of several cell types that are difficult to dissociate while maintaining high cell viability. We describe a protocol for the preparation and dissociation of human buccal and gingival oral mucosal tissue to a high-viability single-cell suspension composed of heterogeneous cell types. This heterogeneous cell suspension can subsequently be used for cytometric analyses or to generate single-cell RNA sequencing libraries. For complete details on the use and execution of this protocol, please refer to Williams et al. (2021).


Subject(s)
Mouth Mucosa/cytology , Single-Cell Analysis/methods , Adult , Cell Survival , Cells, Cultured , Female , Humans , Male , Middle Aged , Young Adult
14.
Science ; 374(6575): eabl5450, 2021 Dec 24.
Article in English | MEDLINE | ID: mdl-34941394

ABSTRACT

Tissue-specific cues are critical for homeostasis at mucosal barriers. Here, we report that the clotting factor fibrin is a critical regulator of neutrophil function at the oral mucosal barrier. We demonstrate that commensal microbiota trigger extravascular fibrin deposition in the oral mucosa. Fibrin engages neutrophils through the αMß2 integrin receptor and activates effector functions, including the production of reactive oxygen species and neutrophil extracellular trap formation. These immune-protective neutrophil functions become tissue damaging in the context of impaired plasmin-mediated fibrinolysis in mice and humans. Concordantly, genetic polymorphisms in PLG, encoding plasminogen, are associated with common forms of periodontal disease. Thus, fibrin is a critical regulator of neutrophil effector function, and fibrin-neutrophil engagement may be a pathogenic instigator for a prevalent mucosal disease.


Subject(s)
Fibrin/metabolism , Mouth Mucosa/immunology , Mouth Mucosa/metabolism , Neutrophil Activation , Neutrophils/immunology , Periodontitis/genetics , Plasminogen/genetics , Alveolar Bone Loss , Animals , Extracellular Traps/metabolism , Female , Fibrin/chemistry , Fibrinogen/metabolism , Fibrinolysin/metabolism , Fibrinolysis , Gastrointestinal Microbiome/physiology , Gingiva/immunology , Humans , Immunity, Mucosal , Macrophage-1 Antigen/metabolism , Male , Mice , Mouth Mucosa/microbiology , Periodontitis/immunology , Plasminogen/deficiency , Plasminogen/metabolism , Polymorphism, Single Nucleotide , RNA-Seq , Reactive Oxygen Species/metabolism
15.
Science ; 373(6561): eabi8835, 2021 Sep 17.
Article in English | MEDLINE | ID: mdl-34529475

ABSTRACT

Puel and Casanova and Kisand et al. challenge our conclusions that interferonopathy and not IL-17/IL-22 autoantibodies promote candidiasis in autoimmune polyendocrinopathy­candidiasis­ectodermal dystrophy. We acknowledge that conclusive evidence for causation is difficult to obtain in complex human diseases. However, our studies clearly document interferonopathy driving mucosal candidiasis with intact IL-17/IL-22 responses in Aire-deficient mice, with strong corroborative evidence in patients.


Subject(s)
Immunity, Mucosal , Mycoses , Humans , Mucous Membrane , Animals , Mice
16.
Science ; 371(6526)2021 01 15.
Article in English | MEDLINE | ID: mdl-33446526

ABSTRACT

Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.


Subject(s)
Candida albicans/immunology , Candidiasis, Chronic Mucocutaneous/genetics , Candidiasis, Chronic Mucocutaneous/immunology , Immunity, Mucosal/immunology , Polyendocrinopathies, Autoimmune/genetics , Polyendocrinopathies, Autoimmune/immunology , Adolescent , Adult , Aged , Animals , Disease Models, Animal , Female , Humans , Immunity, Mucosal/genetics , Immunologic Surveillance/genetics , Immunologic Surveillance/immunology , Interferon-gamma/genetics , Interleukins/genetics , Janus Kinases/genetics , Male , Mice , Mice, Inbred BALB C , Middle Aged , Mouth Mucosa/immunology , Mouth Mucosa/pathology , Receptors, Interleukin-17/genetics , STAT1 Transcription Factor/genetics , T-Lymphocytes/immunology , Young Adult , Interleukin-22
17.
J Exp Med ; 200(10): 1337-46, 2004 Nov 15.
Article in English | MEDLINE | ID: mdl-15545357

ABSTRACT

The distribution of secretory leukocyte protease inhibitor (SLPI) at entry portals indicates its involvement in defending the host from pathogens, consistent with the ability of SLPI to inhibit human immunodeficiency virus (HIV)-1 infection by an unknown mechanism. We now demonstrate that SLPI binds to the membrane of human macrophages through the phospholipid-binding protein, annexin II. Based on the recent identification of human cell membrane phosphatidylserine (PS) in the outer coat of HIV-1, we define a novel role for annexin II, a PS-binding moiety, as a cellular cofactor supporting macrophage HIV-1 infection. Moreover, this HIV-1 PS interaction with annexin II can be disrupted by SLPI or other annexin II-specific inhibitors. The PS-annexin II connection may represent a new target to prevent HIV-1 infection.


Subject(s)
Annexin A2/metabolism , HIV Infections/metabolism , HIV-1/metabolism , Macrophages/metabolism , Phosphatidylserines/metabolism , Proteins/metabolism , Blotting, Western , Cell Line , Chromatography, High Pressure Liquid , DNA Primers , Flow Cytometry , Humans , Immunoprecipitation , Macrophages/virology , Mass Spectrometry , Microscopy, Fluorescence , Proteinase Inhibitory Proteins, Secretory , RNA, Small Interfering/genetics , Reverse Transcriptase Polymerase Chain Reaction , Secretory Leukocyte Peptidase Inhibitor
18.
JCI Insight ; 5(9)2020 05 07.
Article in English | MEDLINE | ID: mdl-32376798

ABSTRACT

Sjögren's syndrome (SS) is a systemic autoimmune disease that mainly affects exocrine salivary and lacrimal glands. Local inflammation in the glands is thought to trigger glandular dysfunction and symptoms of dryness. However, the mechanisms underlying these processes are incompletely understood. Our work suggests T cell exosome-derived miR-142-3p as a pathogenic driver of immunopathology in SS. We first document miR-142-3p expression in the salivary glands of patients with SS, both in epithelial gland cells and within T cells of the inflammatory infiltrate, but not in healthy volunteers. Next, we show that activated T cells secreted exosomes containing miR-142-3p, which transferred into glandular cells. Finally, we uncover a functional role of miR-142-3p-containing exosomes in glandular cell dysfunction. We find that miR-142-3p targets key elements of intracellular Ca2+ signaling and cAMP production - sarco(endo)plasmic reticulum Ca2+ ATPase 2b (SERCA2B), ryanodine receptor 2 (RyR2), and adenylate cyclase 9 (AC9) - leading to restricted cAMP production, altered calcium signaling, and decreased protein production from salivary gland cells. Our work provides evidence for a functional role of the miR-142-3p in SS pathogenesis and promotes the concept that T cell activation may directly impair epithelial cell function through secretion of miRNA-containing exosomes.


Subject(s)
Epithelial Cells , Exosomes , MicroRNAs/physiology , Salivary Glands , Sjogren's Syndrome , T-Lymphocytes , Adenylyl Cyclases/metabolism , Adult , Aged , Calcium Signaling , Cell Line , Epithelial Cells/metabolism , Epithelial Cells/pathology , Exosomes/immunology , Exosomes/metabolism , Female , Humans , Male , Middle Aged , Ryanodine Receptor Calcium Release Channel/metabolism , Salivary Glands/immunology , Salivary Glands/metabolism , Salivary Glands/pathology , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Sjogren's Syndrome/immunology , Sjogren's Syndrome/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Young Adult
19.
JCI Insight ; 3(17)2018 09 06.
Article in English | MEDLINE | ID: mdl-30185668

ABSTRACT

Studies in patients with genetic defects can provide unique insights regarding the role of specific genes and pathways in humans. Patients with defects in the Th17/IL-17 axis, such as patients harboring loss-of-function STAT3 mutations (autosomal-dominant hyper IgE syndrome; AD-HIES) present with recurrent oral fungal infections. Our studies aimed to comprehensively evaluate consequences of STAT3 deficiency on the oral commensal microbiome. We characterized fungal and bacterial communities in AD-HIES in the presence and absence of oral fungal infection compared with healthy volunteers. Analyses of oral mucosal fungal communities in AD-HIES revealed severe dysbiosis with dominance of Candida albicans (C. albicans) in actively infected patients and minimal representation of health-associated fungi and/or opportunists. Bacterial communities also displayed dysbiosis in AD-HIES, particularly in the setting of active Candida infection. Active candidiasis was associated with decreased microbial diversity and enrichment of the streptococci Streptococcus oralis (S. oralis) and S. mutans, suggesting an interkingdom interaction of C. albicans with oral streptococci. Increased abundance of S. mutans was consistent with susceptibility to dental caries in AD-HIES. Collectively, our findings illustrate a critical role for STAT3/Th17 in the containment of C. albicans as a commensal organism and an overall contribution in the establishment of fungal and bacterial oral commensal communities.


Subject(s)
Dysbiosis , Job Syndrome/immunology , Microbiota/immunology , Mouth Mucosa/microbiology , STAT3 Transcription Factor/metabolism , Adult , Candida albicans , Candidiasis , Dental Caries/microbiology , Female , Humans , Interleukin-17 , Job Syndrome/genetics , Male , Microbiota/genetics , Middle Aged , Mutation , RNA, Ribosomal, 16S , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/immunology , Streptococcus mutans , Streptococcus oralis , Th17 Cells , Young Adult
20.
Sci Transl Med ; 10(463)2018 10 17.
Article in English | MEDLINE | ID: mdl-30333238

ABSTRACT

Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, we demonstrate an expansion of resident memory T helper 17 (TH17) cells in human periodontitis. Phenocopying humans, TH17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral TH17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)-dependent manner, periodontitis-associated expansion of TH17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23. TH17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of TH17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in TH17 cell differentiation established human relevance for our murine experimental studies. In the oral cavity, human TH17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Our study highlights distinct functions of TH17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis.


Subject(s)
Dysbiosis/immunology , Dysbiosis/microbiology , Microbiota , Mouth Mucosa/immunology , Mouth Mucosa/pathology , Th17 Cells/immunology , Animals , Bacteria/metabolism , Bone Resorption/microbiology , Bone Resorption/pathology , Bone Resorption/prevention & control , Cell Differentiation , Humans , Inflammation/immunology , Inflammation/pathology , Interleukin-23/metabolism , Interleukin-6/metabolism , Mice , Neutrophils/metabolism , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Periodontitis/immunology , Periodontitis/microbiology , Periodontitis/pathology
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